Serca2 therapeutic compositions and methods of use

Abstract

The present invention provides methods for treating urinary incontinence, urethral sphincter dysfunction and/or bladder dysfunction by delivering a therapeutic adeno-associated virus (AAV)-SERCA2 composition to a subject in need thereof.

1 . A method for treating urinary incontinence in a subject comprising delivering a viral expression vector comprising a transgene into the subject, wherein the transgene modulates Ca +2  ion transport, and wherein expression of the transgene increases host cell function, thereby treating urinary incontinence. 
   
   
       2 . The method of  claim 1 , wherein the host cells are associated with micturation. 
   
   
       3 . The method of  claim 3 , wherein the host cells are selected from the group consisting of urethral sphincter muscle cells, urinary bladder muscle cells, pelvic floor muscle cells, detrusor muscle cells, and abdominal muscle cells. 
   
   
       4 . The method of  claim 3 , wherein the cells are urethral sphincter muscle cells. 
   
   
       5 . The method of  claim 3 , wherein the cells are pelvic floor muscle cells. 
   
   
       6 . The method of  claim 3 , wherein the cells are detrusor muscle cells. 
   
   
       7 . The method  claim 1 , wherein the vector is an adeno-associated vector (AAV). 
   
   
       8 . The method of  claim 7 , wherein the AAV vector is serotype 1 (AAV1) or serotype 2 (AAV2). 
   
   
       9 . The method of  claim 1 , wherein the transgene is sarcoplasmic reticulum (SR) calcium ++  ATpase (SERCA). 
   
   
       10 . The method of  claim 1 , wherein the transgene is SERCA isoform 2 (SERCA2). 
   
   
       11 . The method of  claim 10 , wherein the SERCA2 is SERCA2a. 
   
   
       12 . The method of  claim 1 , wherein the transgene is an S16E mutant of phospholamban. 
   
   
       13 . The method of  claim 1 , wherein the subject suffers from urinary incontinence. 
   
   
       14 . The method of  claim 13 , wherein the subject suffers from stress urinary incontinence (SUI). 
   
   
       15 . The method of  claim 14 , wherein the treatment increases leak-point pressure (LPP) in the bladder. 
   
   
       16 . The method of  claim 1 , wherein the subject is a mammal. 
   
   
       17 . The method of  claim 16 , wherein the subject is a human. 
   
   
       18 . A method for treating urinary bladder dysfunction in a subject comprising delivering a recombinant adeno-associated virus (AAV) virion to the subject, wherein the virion comprises an AAV vector comprising a transgene operably linked to control elements that direct expression of the transgene in a host cell, and wherein the expression of the transgene improves bladder function. 
   
   
       19 . The method of  claim 18 , wherein the transgene is sarcoplasmic reticulum (SR) calcium ++  ATpase (SERCA). 
   
   
       20 . The method of  claim 18 , wherein the transgene is SERCA2. 
   
   
       21 . The method of  claim 18 , wherein the transgene is an S16E mutant of phospholamban. 
   
   
       22 . The method of  claim 18 , wherein the transgene encodes an RNAi which decreases the expression or activity of PLB. 
   
   
       23 . A method for delivering a recombinant adeno-associated virus (rAAV) virion containing a transgene to a muscle cell or muscle tissue of a mammalian subject with urinary incontinence, comprising providing a recombinant AAV virion comprising a polynucleotide encoding a protein or RNAi capable of regulating a calcium cycling pathway of the muscle cell or muscle tissue, wherein the polynucleotide is operably linked to a control element capable of directing expression of the protein or RNAi; and
 delivering the rAAV virion directly into the muscle cell or muscle tissue of the subject, wherein the protein is expressed at a therapeutically effective level in the muscle cell or muscle tissue.   
   
   
       24 . The method of  claim 23 , wherein the protein is sarcoplasmic reticulum (SR) calcium ++  ATpase (SERCA) SERCA. 
   
   
       25 . The method of  claim 24 , wherein the SERCA is SERCA2. 
   
   
       26 . The method of  claim 23 , wherein the protein is an S16E mutant of phospholamban. 
   
   
       27 . The method of  claim 23 , wherein the polynucleotide encodes an RNAi which decreases the expression or activity of PLB. 
   
   
       28 . The method of  claim 23 , wherein the subject is a human.